Cells of the Immune System
The cells of the immune system originate in the bone marrow, where many of them also mature. They then migrate to patrol the tissues, circulating in blood and in a specialized system of vessels called the lymphatic system.
All the cellular elements of blood including the red blood cells, platelets, and white blood cells of the immune system derive ultimately from the same progenitor or precursor cells, the hematopoietic stem cells in the bone marrow. As these stem cells can give rise to all of the different types of blood cells, they are often referred to as pluripotent hematopoietic stem cells. Initially, they give rise to stem cells of more limited potential which include: i) erythroblasts which give rise erythrocytes or red blood cells, ii) megakaryocytes which are the precursors of platelets, iii) myeloid progenitors which are precursors of the granulocytes, macrophages and mast cells of the innate immune system, and iv) the common lymphoid progenitors which give rise to lymphocytes which are the main components of the adaptive immune systems.
There are two main types of lymphocytes: B lymphocytes or B cells, which when activated differentiate into plasma cells, and T lymphocytes or T cells, of which there are two main classes. Within the T cells, one class differentiate into cytotoxic T cells which kill virally infected cells, whereas the second class differentiate into helper T cells. Helper T cells provide help to the adaptive immune system by activating other lymphocytes such as B cells, and interact with the innate immune system by activating some of the myeloid lineage cells. Although all lymphocytes originate within the bone marrow, which is a primary or central lymphoid organ in humans, only B lymphocytes mature there. T lymphocytes migrate to the thymus, the other central lymphoid organ in humans, to undergo maturation.
Both B and T cells express on their surface, specialized receptors that allow them to recognize antigens. Although collectively these receptors are highly diverse in their antigen specificity, each fully differentiated lymphocyte, and all its progeny, is designed to express receptors that recognize only one antigen. Collectively, the receptors on all the lymphocytes are capable of recognizing a very large repertoire of antigens. The B-cell antigen receptor (BCR) is a membrane-bound form of the antibody that will be secreted when the cells are activated. The T cell antigen receptor (TCR), although related to BCR because of their common structural immunoglobulin roots, is quite distinct from BCR in its antigen binding region, and in the way it interacts with the antigen. A third class of lymphoid cells, called natural killer cells or NK cells, lack antigen-specific receptors and so form part of the innate immune system.
Mature antigen-responsive B lymphocytes develop in the bone marrow prior to their encounter with antigen. The maturation process goes through an orderly series of differentiation stages from the common lymphoid progenitors through the pro-B, pre-B, transitional or immature B, to mature B lymphocytes. Following their encounter with antigen, B cells undergo antigen-induced proliferation and differentiation whose hallmark is the re-arrangement of the immunoglobulin gene locus and expansion of B cell clones. This process ultimately results in the progeny of the B cells secreting antibodies of different heavy and light chain isotypes, or becoming memory cells.
Hematologic Malignancies
With respect to pathological conditions which involve the immune system, the diversity in the lineages and differentiation stages of hematopoietic cells results in a large number of distinct and heterogeneous tumors generally referred to as hematologic malignancies. Thus, hematologic malignancies or hematologic neoplasia affect cells and tissues of the immune and hematopoietic system, including blood, bone marrow and lymph nodes. Hematologic malignancies include both leukemias and lymphomas.
The term leukemia has generally been used to define hematologic malignancies of the blood or bone marrow characterized by abnormal proliferation of leukocytes. The principal subtypes of leukemia are identified on the basis of malignancy involving lymphoid (e.g. T or B lymphocytic lineage) or myeloid (e.g. granulocytic, erythroid or megakaryocytic lineage) cells, and whether the disease is acute or chronic in onset [Freireich, E. J. et al., 1991].
The term lymphoma covers a heterogeneous group of neoplasms of lymphoid tissue. Lymphomas are broadly categorized under Hodgkin lymphoma, and T-cell (T-NHL) and B-cell (B-NHL) non-Hodgkin lymphomas. A World Health Organization (WHO) classification has recently been published (discussed later in this application), and diagnostic guidelines have been established based on this classification [Jaffe, E. S. et al., 2004 (see Table 3 and 4 hereinafter)].
Chronic Lymphocytic Leukemia (CLL) is a form of lymphocytic leukemia characterized by slow but progressive accumulation of lymphocytes in the bone marrow and blood. Depending on the stage of the disease, lymph node and spleen enlargement occur commonly. Although CLL may be of T cell or B cell origin, over 85% of the cases are of B-cell origin. Current understanding suggests that CLL is a heterogeneous disease originating from B lymphocytes that differ in their activation and maturation states and cellular subgroup (see [Kuppers, R., 2005]). The disease may result both from decreased apoptosis as well as increased proliferation of the leukemic B cells. CLL cells are usually clonal in origin, and express the following cell surface markers: CD19, CD20, CD21, and CD24. In addition, they express CD5 which is more typically found on T cells (see [Chiorazzi, N, and al., 2005]).
CLL is considered a subgroup of “non-Hodgkin's lymphoma” (NHL) and together with the closely related disease “small lymphocytic lymphoma” (SLL) which presents primarily in the lymph nodes, corresponds to around 20% of all NHL cases. CLL is the most common leukemia in adults in the US and most of Western Europe. The National Cancer Institute (NCI) estimate for the incidence of CLL is about 10.000 new cases in the US per year. Clinical manifestations of CLL occur predominantly after the age of 55. The incidence rate for men is higher than for women, with men almost twice as likely to acquire the disease as women.
CLL represents an unmet medical need as there are limited options for treatment
The most common treatments for NHL are chemotherapy, in particular a combination regimen called CHOP (for Cytoxan, Hydroxyrubicin [Adriamycin], Oncovin [Vincristine], Prednisone), and radiation therapy. In some cases, surgery and bone marrow transplantation have also been used. More recently, there has been an increase in the use of biopharmaceutical agents, especially monoclonal antibodies, such as rituximab and alemtuzumab. Other combination approaches include the use of biopharmaceuticals such as rituximab with chemotherapy. Although these treatments have significantly improved the management of B-lymphoid malignancies, among their deficiencies include non-responsiveness of many patients to these regimens (some patients become refractory to some or all these approaches), and the side effects and complications which result from the use of these treatments. Among the most common side effects of chemotherapy are nausea and vomiting (which is generally managed with the use of antiemetics), alopecia (which is generally reversed over time after completion of treatment), and leukopenia, especially neutropenia. Neutropenia generally develops in the second week. During this period, many clinicians recommend prophylactic use of ciprofloxacin. If a fever develops in the neutropenic period, urgent medical assessment is required for neutropenic sepsis, as infections in patients with low neutrophil counts may progress rapidly. With respect to rituximab, first infusion reaction, lymphopenia, infectious complications such as viral reactivation including Hepatitis B and Progressive Multifocal Leukoencephalopathy (PML), mucocutaneous reactions, and renal complications have been reported. In the case of alemtuzumab, serious hematologic toxicities can occur, including pancytopenia, bone marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia. In some cases, these toxicities can accelerate morbidity and mortality rates.
Autoimmune Diseases
The immune system has control mechanisms which prevent it from attacking self tissue. When these mechanisms do not function properly or when they break down, they can result in the development of autoimmunity or autoimmune diseases. Autoimmunity represents a broad spectrum of diseases from the organ specific to the non-organ specific. At one end of the spectrum, Hashimoto's thyroditis typifies the highly organ specific diseases where the destructive lesion is directed at one organ only. At the other end of the spectrum, lupus erythomatosus (SLE) represents the non-organ specific diseases where the tissues involved are widespread throughout the body. With improvements in our understanding of immunobiology, and advances in molecular and diagnostic tools, it is becoming progressively evident that most organ or tissue systems can be subject to the autodestructive potential of autoimmune diseases as is shown in the following list. Thus among the autoimmune diseases are included: Addison's disease, ankylosing spondylitis, aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease, dermatomyositis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, idiopathic leucopenia, idiopathic thrombocytopenic purpura, insulin dependent diabetes mellitus (Type 1 diabetes), male infertility, mixed connective tissue disease, multiple sclerosis (MS), myasthenia gravis, pemphigoid, pemphigus vulgaris, pernicious anemia, phacogenic uveitis, primary biliary cirrhosis, primary myxoedema, Reiter's syndrome, rheumatoid arthritis (RA), scleroderma, Sjögren's syndrome, stiff man syndrome, systemic lupus erythematosus (SLE), thyrotoxicosis, ulceritive colitis, and Wegener's granulomatosis.
The etiology of autoimmune diseases is not completely understood. In some instances, mechanisms of molecular mimicry have been proposed whereby a productive anti-bacterial or anti-viral response may inadvertently result in the development of immunological responses to self tissue. In addition, inherited or genetic predispositions are known to contribute to the development of many of these diseases.
Both lymphoid and myeloid lineage cells have been implicated in the development of autoimmune diseases. Autoreactive T and B lymphocytes determine the principal clinico-pathologic features of each disease and the tissue involved. T lymphocytes may attack self tissue directly whereas B cells secrete autoreactive antibodies. In SLE, copious of self reactive antibodies including antibodies to double-stranded DNA are produced which are believed to cause or exacerbate kidney damage. Myeloid lineage cells such are macrophages help to maintain, amplify and extend the immune attack against self tissue by providing cytokine and chemokine responses such as TNF-α and IL-8, as well as by serving as effector cells for the autodestructive processes. A role for TNF-α has been clearly established for RA and Crohn's disease which are now known to respond to anti-TNF-α therapies. In the case of RA, myeloid lineage cells are believed to differentiate to osteoclasts thus causing bone damage and destruction of synovial linings with the inflamed joints. RA patients have also been shown to respond to treatments directed against B cells, such as anti-CD20 antibody therapy.